ABSTRACT Alcoholic hepatitis (AH) is the most severe form of alcohol-induced organ damage in the liver with clinical manifestations of severe liver disease and high mortality. The precipitating factors and determinants of clinical outcome remain elusive in AH. The clinical outcome of AH depends on key factors such as 1) impaired host defense in the alcoholic patient that predisposes to infections; 2) systemic inflammation in AH that contributes to the development of Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure; and 3) the regenerative capacity of the liver. In this proposal, we aim to answer critical questions related to these key determinants of clinical outcomes using bedside to bench approaches. We will utilize biospecimens prospectively collected in the AlcHepNet clinical trial in the observational study (Aim#1) to evaluate the functional, phenotypic and metabolomics characteristics of major circulating immune cell populations in the well-defined patient populations in this study: severe AH, moderate AH, heavy drinkers without evidence of clinical liver disease, and normal control. Samples from the Late Stage Clinical Trial that include the treatment arms of prednisone, IL- 1receptor antagonist (IL-1ra, also known as anakinra, plus zinc) and G-CSF will be utilized to gain mechanistic insights into these novel treatments through translational research. Because these interventions target elements of inflammation, immune responses and/or liver regeneration, evaluation of the prospectively collected biospecimens will provide a valuable tool for mechanistic ex vivo studies that complement the clinical observations collected in the main clinical trial. The AlcHepNet clinical trial will collect clinical data on well-defined patient and control populations linked with unique biospecimens to support high-quality translational research and address some of the most burning clinical questions in AH. The Specific Aims are: Aim #1: To assess alcohol-induced immunosuppression and dysregulated innate immune responses to pathogen-derived signals in relation to the natural history, infections and clinical outcomes in patients with AH using samples from the AlcHepNet Observational Study. Aim #2: To test the biological consequences of novel therapies with IL-1ra and G-CSF on innate immune activation, markers of gut leakiness and circulating markers of liver regeneration using prospectively collected samples from the AlcHepNet Late Stage Clinical Trial. ! !